The goals of this project involve use of a multidisciplinary integrative approach to the understanding of development and regression of myocardial hypertrophy. During this funding period, we have shown a fundamental defect in the molecular composition the heart during hypertrophy. We have shown that: a) an increase in deposition of collagen and its phenotypes occurs during the chronic phase of hypertrophy; b) stiffness of the heart may depend on the type(s) of collagen produced in the heart; c) fibroblasts play an important role (we identified a factor present in fibroblasts that stimulates collagen production and myocyte growth); and d) after regression of hypertrophy, in a small heart, the capability of tolerating stress depends upon the type of antihypertensive treatment used. Our preliminary data showed that captopril therapy enabled the heart to tolerate stress when exposed to sudden increase in dobutamine-induced stress, whereas treatment with beta-blocker or hydralazine failed to do so. All these observations generated several new questions, and we have designed this renewal proposal to continue to study the interstitial matrix. We hypothesize that due to long-standing hypertension associated with increased sympathetic overdrive, fibroblasts alter their phenotypes and deposit disproportionately increased amounts of collagen with changed phenotypes. This results in excessive fibrosis and reduced compliance, progressing to heart failure. In this continuation proposal spanning the next 5 years, we continue to focus on collagen production by fibroblasts with the following specific aims: 1) evaluate the role of fibroblasts on myocardial hypertrophy; 2) identify production by fibroblasts of factors that modulate collagen and its phenotypes; 3) evaluate the role of hypertension on collagen production and quantify the alteration of collagen and its phenotypes in hypertensive rats during chronic hypertrophy and after prevention of hypertension by antihypertensive therapy; and 4) correlate the molecular changes observed to cardiac function. These studies will utilize a variety of morphological, biochemical and molecular techniques to analyze dynamic changes that occur in the extracellular matrix, especially regarding collagen and its phenotypic gene expression during development and regression of myocardial hypertrophy. These studies are expected to outline the abnormalities of collagen formation during development and regression of hypertrophy and its transition to heart failure with special emphasis on the factor(s) responsible for altered collagen production and elucidate the importance of crosstalk between cell types in controlling myocyte growth and collagen deposition in the myocardium. Upon identifying the derangement, appropriate treatment can be prescribed to correct the abnormalities, and to determine if such directed alteration in the myocardial collagen formation by appropriate therapy improves the compromised function of the hypertrophied heart.